Multiple sclerosis (MS) is a devastating human autoimmune disease that primarily affects females in the third decade of life resulting in a variety of neurological symptoms including problems with motor function, vision, sphincter control and memory. MS is associated with inflammatory lesions in the central nervous system (CNS) that contain large numbers of cells from the immune system that are thought to contribute to the demyelination and axonal loss associated with the disease. Control of the CNS inflammation is critical to the control of MS symptoms and pathogenesis as it is the inflammatory response that is thought to directly cause the neurological symptoms and damage. Thus it is essential to understand how inflammation is controlled in the CNS if new targeted therapies are to be developed for MS treatment. In our studies using an animal model of MS, experimental autoimmune encephalomyelitis (EAE), we have observed that the B lymphocyte, or B cell, is required for recovery from disease symptoms. We have also observed that B cell expression of the co-stimulatory molecules B7 and CD40, and their production of IL-10 are required for recovery. We have also found that B7 expression is required for the timely appearance of Foxp3 T regulatory (Treg) cells and IL-10 in the CNS during EAE. These data demonstrate that B cells are required for the resolution of CNS inflammation. This proposal will investigate these B cell regulatory mechanisms by testing the following hypothesis: CD40-stimulated B cells activate a population of Treg cells via B7/CD28 and IL-10 in the periphery that in turn enter the CNS and suppress inflammation by an IL-10-dependent mechanism. This hypothesis will be tested by three aims: 1) To Identify the IL-10 producing B cell subset(s) required for EAE resolution; 2) To identify the B cell-derived immunological signals that promote their production of IL-10 and the presence of IL-10 and Treg in the CNS; and 3) To Identify the T cell subset(s) that interact with the regulatory B cells. We will be identifying the IL-10-producing B cell subset; the regulatory mechanisms induced by B cell derived B7, CD40 and IL-10; the required T cell populations and the IL-10 producing cell in the CNS. Specifically, these studies are designed to determine how B cells either directly or indirectly through interactions with T cells, drive the resolution of inflammation in the CNS. Since little is known about how B cells regulate inflammation, these studies are likely to have an impact on multiple human inflammatory diseases, in addition to MS. It is our hope that the insight gained into how inflammation is regulated in the CNS will aid in the development of therapies for MS and other diseases that are inflammatory in nature.Public Health Relevance Statement In the central nervous system of multiple sclerosis patients the immune system facilitates the development of inflammatory lesions that result in permanent tissue damage resulting in disability if not resolved. B cells have been shown to regulate this autoimmune inflammation in the animal model of multiple sclerosis. This proposal will investigate the cellular mechanisms utilized by regulatory B cells in the resolution of central nervous system inflammation resulting in recovery from disease.